Aniline analeptics

ABSTRACT

This invention concerns compounds of the formula: ##STR1## and the N-oxides and the pharmaceutically acceptable salts thereof wherein R 1  is phenyl unsubstituted or substituted by fluoro chloro, bromo, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms; 
     R 2  is hydrogen or alkyl of 1 to 4 carbon atoms; 
     R 3  is hydrogen, nitro, amino, ##STR2##  in which R 4  is alkyl of 1 to 4 carbon atoms unsubstituted or substituted with up to three chlorine atoms or with three fluorine atoms on the same carbon atoms; 
     R 5  is alkyl of 1 to 4 carbon atoms 
     n has a value of 0, 1 or 2.

This application is a division of Ser. No. 894,942, filed Apr. 10, 1978,now U.S. Pat. No. 4,223,034.

The present invention relates to aniline derivatives possessing majortranquillizing activity, to pharmaceutical compositions containing them,to the process for their preparation and to intermediates useful in thatprocess.

Metoclopramide, which is the chloroaniline derivative of the formula(I): ##STR3## has found widespread clinical use due to its ability toenhance the rate of gastric emptying. A structurally distinct group ofchloroaniline derivatives has now been found which possess a differentpharmacological activity, namely major tranquillizing activity.

The present invention provides the compounds of the formula (II):##STR4## wherein R₁ is a phenyl group optionally substituted by afluorine, chlorine or bromine atom or an alkyl or alkoxyl group of up to3 carbon atoms; R₂ is a hydrogen atom or an alkyl group of up to 4carbon atoms; R₃ is a hydrogen atom or an amino group, a nitro group ora group of the formula NHCOR₄ or NHCO₂ R₄ where R₄ is an alkyl group ofup to 4 carbon atoms optionally substituted by one, two or threechlorine atoms or by three fluorine atoms attached to the same carbonatom; n is 0, 1 or 2; and X is a group of the sub-formula (a), (b), (c)or (d): ##STR5## wherein R₅ is an alkyl group of up to 4 carbon atoms;or a N-oxide thereof of the nitrogen atom to which the CHR₂ --(CH₂)_(n)--R₁ moiety is attached; or a salt thereof.

Suitably R₁ is a phenyl, p-chlorophenyl, p-methylphenyl, p-methoxyphenylor like group.

Preferably R₁ is a phenyl group.

Suitably R₂ is a hydrogen atom or a methyl, ethyl, n-propyl or n-butylgroup.

More suitably R₂ is a hydrogen atom or a methyl group.

Preferably R₂ is a hydrogen atom.

Most suitably n is 0.

From the foregoing it will be realised that a favoured CHR₂ --(CH₂)_(n)--R₁ moiety is the benzyl group.

Suitably R₃ is a hydrogen atom. Compounds in which R₃ is a hydrogen atomare envisaged primarily as intermediates.

Suitably R₃ is a nitro group. Compounds in which R₃ is a nitro group areenvisaged primarily as intermediates.

Suitably R₃ is an amino or NHCOR₄ group where R₄ is an alkyl group of upto 4 carbon atoms. Compounds in which R₃ has one of these meanings areenvisaged as pharmacologically active compounds and especially when R₃is an amino group.

More suitably R₃ is an amino group or alternatively an acetylamino,propionylamino, methoxycarbonylamino, ethoxycarbonylamino or like group.

Most suitably R₃ is an amino or acetylamino group.

Preferably R₃ is an amino group.

One group of favoured pharmacologically active compounds of the formula(II) is that of the formula (III): ##STR6## wherein X is as defined inrelation to formula (II) and salts thereof.

A further group of favoured pharmacologically active compounds of theformula (II) is that of the formula (IV): ##STR7## and salts thereofwherein R₁, R₂, and n are as defined in relation to formula (II) and R₆is a hydrogen atom or a COR₄ or CO₂ R₄ group where R₄ is as defined inrelation to formula (II).

Particularly suitable values for R₁, R₂ and n are as described inrelation to the compounds of the formula (II).

The compounds of the formula (IV) wherein CHR₂ --(CH₂)_(n) --R₁represents a benzyl group have especially favourable neurolepticactivity but do not have a high level of disadvantageous side effects onthe gastro intestinal system.

Since the compounds of the formula (II) are nitrogenous bases they areable to form acid addition salts in a conventional manner. Most suitablythese salts are those formed with pharmaceutically acceptable inorganicor organic acids such as hydrochloric, hydrobromic, orthophosphoric,methanesulphonic, toluenesulphonic, acetic, fumaric, tartaric, lactic,citric, succinic or the like acid. Those compounds of the inventionwhich contain more than one basic nitrogen atom may form di-acidaddition salts as well as mono-acid addition salts, for example thedihydrochloride salt as well as the monohydrochloride salt.

The present invention also provides a pharmaceutical composition whichcomprises a compound of this invention and a pharmaceutically acceptablecarrier.

Most suitably the compound used in the composition of this inventionwill not be one in which R₃ is a hydrogen atom or a nitro group.Preferably the compound used in the composition of this invention willbe one in which R₃ is an amino group.

The composition of this invention will normally and preferably beadapted for oral administration although parenteral compositions arealso envisaged as useful.

The compositions of this invention will most suitably be presented asunit dose compositions containing from 1 to 200 mg, more usually from 5to 100 mg, for example from 10 to 50 mg such as 12.5, 15, 20, 25 or 30mg. Such compositions will normally be taken from 1 to 6 times daily,for example 2, 3 or 4 times daily so that the total amount of activeagent administered is within the range 5 to 400 mg.

Preferred unit dosage forms include tablets, capsules and theirequivalents.

Injectable compositions of this invention will normally comprise an acidaddition salt of the compound of the invention since the free bases tendto be of disadvantageously low aqueous solubility.

The compositions of this invention may be formulated by conventionalmethods of blending, filling, compressing and the like.

Suitable carriers for use in this invention include diluents, binders,disintegrants, colouring agents, flavouring agents, preservatives andthe like. These agents may be utilized in conventional manner, forexample in a manner similar to that already used for other moodmodifying agents such as clinically used tranquillizing agents.

The present invention also provides a process for the preparation of thecompounds of the formula (II) wherein X is a group of the sub-formula(a) or (d) which process comprises the reaction of the compound of theformula (V): ##STR8## with a reactive acylating derivative of a compoundof the formula (VI):

    HO.sub.2 C--X--CHR.sub.2 --(CH.sub.2).sub.n --R.sub.1      (VI)

wherein R₁, R₂, X and n are as defined in relation to formula (II);thereby producing a compound of the formula (II) wherein R₃ is ahydrogen atom; and thereafter if desired nitrating the compound of theformula (II) wherein R₃ is a hydrogen atom to yield a compound of theformula (II) wherein R₃ is a nitro group; and thereafter if desiredreducing the compound of the formula (II) wherein R₃ is a nitro group toyield a compound of the formula (II) wherein R₃ is an amino group; andthereafter if desired acylating the compound of the formula (II) whereinR₃ is an amino group to yield a compound of the formula (II) wherein R₃is a NHCOR₄ or NHCO₂ R₄ group where R₄ is defined as in relation toformula (II).

Suitable active acylating derivatives of the acid include acid halidessuch as the acid chloride, the acid anhydride, mixed anhydrides such asthose formed from ethyl chloroformate or equivalent reagents, reactivereagents formed by a carbodiimide such as dicyclohexylcarbodiimide, andesters such as the methyl, ethyl and like esters.

The reaction is normally carried out in non-hydroxylic organic solventsuch as tetrahydrofuran, ethyl acetate, toluene, dichloromethane,NN-dimethylformamide and the like. The reaction is normally carried outin the presence of an acid acceptor such as pyridine, triethylamine orthe like. The reaction may be carried out at any non-extreme temperaturesuch as -10°-100° C. and more suitably 0°-80° C. The higher reactiontemperatures are employed with less active derivatives of the acid ofthe formula (VI) such as esters whereas the lower temperatures areemployed with the more reactive derivatives of the acid of the formula(VI) such as mixed anhydrides or the like.

The compound of the formula (II) wherein R₂ is hydrogen may be isolatedfrom the reaction mixture in conventional manner, for example byevaporation of the solvents followed, if desired, by chromatography.

The compounds of the formula (II) wherein R₃ is a nitro group may beprepared by the nitration of the corresponding compound of the formula(II) wherein R₃ is a hydrogen atom.

The reaction may be brought about under reaction conditions known assuitable for the mono-nitration of anisole.

A particularly suitable nitrating agent for use in this process isfuming nitric acid. In general the reagent is added to a solution of thecompound of the formula (II) wherein R₃ is hydrogen, in solution in anorganic solvent such as acetic acid. Normally the reaction is carriedout at an ambient or slightly super ambient temperature, for example15°-45° C. and more suitable at about 30°-40° C.

The nitro compound may be obtained from the reaction mixture by suchconventional means as neutralisation followed by extraction into a waterimmiscible organic solvent such as ethyl acetate from which it may berecovered by evaporation. If desired the nitro compound may be purifiedby chromatography or by recrystallisation of the free base or an acidaddition salt thereof.

A process provided by this invention for the preparation of thecompounds of the formula (II) wherein R₃ is an amino group comprises thereduction of a corresponding compound of the formula (II) wherein R₃ isa nitro group.

The reduction of the compounds of the formula (II) wherein R₃ is a nitrogroup may be effected with reagents known to be suitable for reducingnitroanisole to aminoanisole. A suitable reagent for this reduction isstannous chloride in hydrochloric acid or in mixtures of hydrochloricand acetic acids.

The desired amino compound may be obtained from the reaction mixture byneutralisation followed by extraction into a water immiscible solventsuch as ethyl acetate from which it may be recovered by evaporation ofthe solvent. The initial crude product may be purified by chromatographyor crystallisation or by forming an acid addition salt which may berecrystallised.

Those compounds of the invention wherein R₃ is a NH.CO.R₄ or NH.CO₂ R₄group may be prepared from the corresponding compound of the formula(II) wherein R₃ is an amino group by reaction with an acylatingderivative of the acid of the formula HO₂ C.R₄ or HO₂ C.OR₄. Suitableacylating derivatives are as previously described as suitable acylatingderivatives of the acid of the formula (VI) and the reaction may proceedas described for the reaction of the compounds of the formula (V) and(VI).

The invention provides a further process for the preparation ofcompounds of the formula (II) wherein R₃ is other than an amino groupand X is a group of the sub-formula (b) or (c), which process comprisesthe reaction of a compound of the formula (VII): ##STR9## wherein R₃ *is a group R₃ as defined in relation to formula (II) except an aminogroup, with a compound of the formula (VIII) or (IX): ##STR10## whereinR₁, R₂ and n are as defined in relation to formula (II).

The reaction may be carried out in an aprotic medium at a non-extremetemperature, for example in toluene at room temperature.

The compound of the formula (VII) may be prepared by heating thecorresponding azide, e.g. at 90° in an aprotic solvent such as toluene.The azide may be prepared from the corresponding acid chloride byreaction with sodium azide.

The compounds of the formula (II) wherein R₃ is an amino group are ableto be converted into mono- or di-acid addition salts by mixing insolution the desired quantity of acid with the base of formula (II). Thereaction is generally carried out in a solvent such as in which thestarting materials are soluble but in which the resulting salt isinsoluble.

This invention also provides a process for the preparation of a compoundof the formula (II) wherein R₃ is an amino group atom which comprisesthe deacylation of a corresponding compound of the formula (II) whereinR₃ is a group of the formula NH.CO.R₄ or NHCO₂ R₄ wherein R₄ is asdefined in relation to formula (II).

Generally the hydrolysis reaction may be effected by treatment with abase such as an alkali metal hydroxide in an aqueous alcoholic. Thereaction is usually carried out at an ambient or elevated temperature,for example at about 20°-100°, more usually at about 40°-80°.

In a further aspect this invention provides a process for thepreparation of a compound of the formula (II) wherein X is a group ofthe sub-formula (d) which comprises the reduction of a correspondingcompound of the formula (X): ##STR11## wherein R₁, R₂, R₃ and n are asdefined in relation to formula (II) and Q.sup.⊖ is an anion.

Suitably Q is Cl, Br or I or the chemical equivalent.

The reduction reaction is suitably performed by cataytic hydrogenation.

A medium or high pressure of hydrogen is generally employed, for example50-500 psi, more usually about 200-300 psi.

Normally the catalyst employed is Adams catalyst.

The reaction is usually performed in an alkanolic solvent such asethanol at a non-extreme temperature, for example at ambienttemperature.

In a further process aspect this invention provides a process for thepreparation of a compound of the formula (II) wherein X is a group ofthe sub-formula (a) which comprises the reaction of a correspondingcompound of the formula (XI): ##STR12## wherein R₃ is as defined inrelation to formula (II) with a compound of the formula (XII):

    Q.sub.1 --CHR.sub.2 --(CH.sub.2).sub.n --R.sub.1           (XII)

wherein R₁, R₂ and n are as defined in formula (II) and Q₁ is a group oratom readily displaced by a nucleophile.

Suitable values for Q₁ include Cl, Br, I, OSO₂ CH₃, OSO₂ C₆ H₄ pCH₃ andtheir chemical equivalents.

Particularly suitably the compound of the formula (XI) is a benzylhalide such as benzyl bromide or benzyl chloride.

The reaction may be carried out under conventional alkylation conditionsfor example in an inert solvent such as dimethylformamide in thepresence of an acid acceptor such as potassium carbonate. Generally thereaction is carried out at a non-extreme temperature such as at ambientor at a slightly elevated temperature.

The following Examples illustrate the invention:

EXAMPLE 1 4-Chloro-2-(1¹ -benzylpiperidine-4-carboxamido)-anisole##STR13##

A mixture of 2-amino-4-chloro-anisole (e1) (10 g),N-benzyl-piperidine-4-carboxylic acid (13.9 g) anddicyclohexylcarbodiimide (13.15 g) in dichloromethane (250 ml) andtetrahydrofuran (250 ml) was stirred for 24 hours. The mixture was thenfiltered and evaporated to dryness. Ether was added to the residue andthe solution again filtered and the clean solution evaporated. Theresidue was chromatographed on silica gel eluting with progressivelygraded mixtures of light petroleum, ether and ethyl acetate.4-Chloro-2-(1¹ -benzylpiperidine-4-carboxamido)anisole (e2) (12 g, 53%),m.p. 85°-87° C. was obtained, characterised further as the hydrochloridehydrate, m.p. 155°-157° C.

EXAMPLE 2 4-Chloro-2-(1¹ -benzylpiperidine-4-carboxamido)-5-nitroanisole##STR14##

Fuming nitric acid (5 ml) was added dropwise with stirring to a solutionof 4-chloro-2-(1¹ -benzylpiperidine-4-carboxamido)anisole (e2) (4 g) inacetic acid (20 ml) keeping the temperature below 35° C. After 4 hoursthe solution was poured into water, basified (with 40% NaOH solution)and extracted with ethyl acetate. On evaporation, 4-chloro-2-(1¹-benzylpiperidine-4-carboxamido)-5-nitroanisole (e3) (3.5 g, 78%) wasobtained which was later characterised as the hydrochloride m.p. 194°-5°C. (recrystallised from ethanol-ether).

Similarly prepared were (a)4-chloro-2-[1-(2-phenyl)ethylpiperidine-4-carboxamido]-5-nitroanisole(70%), cream prisms, m.p. 131°-132°; (b)4-chloro-2-[1-(4-chlorobenzyl)-piperidine-4-carboxamido]-5-nitroanisole(89%), brown prisms, m.p. 158°-161°; and (c)4-chloro-2-[1-(4-methylbenzyl)-piperidine-4-carboxamido]-5-nitroanisole(65%), yellow prisms, m.p. 171°-173°.

EXAMPLE 3 5-Amino-4-chloro-2-(1¹-benzylpiperidine-4-carboxamido)-anisole ##STR15##

4-Chloro-2-(1¹ -benzylpiperidine-4-carboxamido)-5-nitroanisole (e3)(6.44 g) was added in portions to a solution of stannous chloridedihydrate (10.82 g) in concentrated hydrochloric acid (40 ml). Themixture was stirred at 40° C. for 1 hour. The mixture was then filteredand the filtrate poured on to ice and basified. Extraction with ethylacetate gave an oil which was chromatographed on silica gel eluting withprogressively graded mixtures of light petroleum, ether and ethylacetate. 5-Amino-4-chloro-2-(1¹ -benzylpiperidine-4-carboxamido)-anisole(e4) was obtained. n.m.r. (CDCl₃) τ 1.72 (1H, s, 3-aromatic-H), 2.48(1H, broad s, NHCO), 2.70 (5H, s, aromatic-H) 3.70 (1H, s,6-aromatic-H), 6.08 (2H, broad s, NH₂), 6.20 (3H, s, OCH₃), 6.48 (2H, s,N--CH₂ Ph), 6.88-8.38 (9H, broad multiplets, piperidine ring --H).

This free base was converted to a hydrochloride (1.5 g, 23%).

EXAMPLE 4 5-Amino-4-chloro-2-(1¹ -benzylpiperidine-4-carboxamido)anisole##STR16##

4-Chloro-2-(1¹ -benzylpiperidine-4-carboxamido)-5-nitroanisole (e3)(15.4 g) was dissolved in acetic acid (150 ml) at room temperature. Tothis was added a solution of stannous chloride (21.7 g of anhydrous) inconcentrated hydrochloric acid (50 ml). The mixture was stirredovernight at ambient temperature (˜20°). The resulting clear solutionwas poured onto ice and the solution was rendered strongly basic with40% NaOH solution (total volume at this stage was about 2 l). Themixture was extracted with ethyl acetate (2×150 ml). The organic phasewas passed through a 2.5 cm×20 cm column of alumina. The resultingsolution was evaporated to dryness to yield a buff foam (12.9 g). n.m.r.(CDCl₃) τ 1.78 (1H, s, 3-aromatic-H), 2.50 (1H, broad, s, NH.CO), 2.75(5H, s, aromatic-H), 3.76 (1H, s, 6-aromatic-H), 6.09 (2H, broad, s, NH₂), 6.24 (3H, s, OCH₃), 6.52 (2H, s, N--CH₂ C₆ H₅), 6.85-7.26 (2H, broadmultiplet, piperidine ring H), 7.57-8.49 (7H, broad multiplet,piperidine ring H).

A sample of the foam (2.0 g) was recrystallised by dissolving in hotether and adding petroleum ether (60°-80°) until the solution wasopalescent and then allowed to cool. The resulting buff crystals werefiltered off, washed with petrol (60°-80°) and dried to yield 1.4 g ofthe desired compound (e4) as buff prisms, m.p. 105°-6° C.

    ______________________________________                                        Analysis   Required       Found                                               ______________________________________                                        C          64.24          64.50   64.13                                       H          6.47           6.98     6.85                                       N          11.23          11.15   11.15                                       Cl         9.50           9.81    10.03                                       ______________________________________                                    

EXAMPLE 5 5-Amino-4-chloro-2-(4-N-benzyl-piperidinecarbonylamino)anisoledihydrochloride ##STR17##

The nitroanisole (e3) (14.7 g) was dissolved in acetic acid/concentratedhydrochloric acid (1:1, 150 ml). To this solution was added a solutionof stannous chloride (20.8 g) in concentrated hydrochloric acid (50 ml).The reaction mixture was warmed to 60° C. and stirred for 1 hour at theend of which time the solution had returned to ambient temperature. Thesolution was poured onto ice and basified with sodium hydroxide solution(40%) to give a final volume of about 2 l. The mixture was extractedwith ethyl acetate (2×150 ml) and the organic phase dried (potassiumcarbonate) and filtered to give a clear solution. To this solution wasadded excess ethereal HCl to precipitate a di-hydrochloride salt. Thiswas dissolved in water, the resulting solution washed with ethylacetate, basified with sodium hydroxide solution and extracted intoethyl acetate. The organic phase was dried (potassium carbonate) and thesolvent evaporated to yield a brown oil (7.4 g).

The oil was dissolved in ether (100 ml) and excess of ethereal HCl wasadded. A solid precipitated and this was filtered off, washed with etherand transferred to a vacuum oven at 60° C. and dried thoroughly. Thecompound was further purified by dissolving in hot isopropanol andallowed to cool. The resulting off white solid was filtered off anddried in the vacuum oven at 60° C. to yield the desired product (e5)(5.6 g) which decomposed above 180° C.

    ______________________________________                                        Analysis        Required Found                                                ______________________________________                                        C               53.73    53.96                                                H               5.86     5.94                                                 N               9.40     9.43                                                 ______________________________________                                    

In a similar fashion were prepared:

(a)5-amino-4-chloro-2-(1-(2-phenylethyl)piperidine-4-carboxamido)anisole asa brown oil (25%); n.m.r. (CDCl₃) τ 1.76 (1H, s, 3-aromatic-H), 2.29(1H, broad s, NHCO), 2.76 (5H, s, aromatic H), 3.70 (1H, s,6-aromatic-H) 5.40-5.79 (2H, broad singlet, NH₂), 6.27 (3H, s, OCH₃(6.71-8.43 (13H, broad multiplets, piperidine ring--H and NCH₂ CH₂ Ph).Treatment with excess ethereal HCl gave a dihydrochloride, whichdecomposed at about 180°-210°.

(b)5-amino-4-chloro-2-(1-(4-chlorobenzyl)piperidine-4-carboxamido)anisoleas a brown oil (46%). n.m.r. (CDCl₃), τ 1.78 (1H, s, 3-aromatic-H), 2.48(1H, broad s, NHCO), 2.77 (4H, s, aromatic H), 3.73 (1H, s,6-aromatic-H), 6.02 (2H, broad s, NH₂), 6.22 (3H, s, OCH₃), 6.55 (2H, s,N--CH₂ --Ar), 6.35-7.28 (2H, broad multiplet, piperidine ring H),7.63-8.22 (7H, broad multiplet, piperidine ring H). The compound wasconverted to a di-hydrochloride as described above. to yield adihydrochloride, which decomposed at about 180°-210°.

(c)5-amino-4-chloro-2-(1-(4-methylphenyl)piperidine-4-carboxamido)anisoleas a brown oil, (72%); n.m.r. (CDCl₃) τ 1.74 (1H, s, 3-aromatic-H) 2.48(1H, broad s, NHCO), 2.65-3.01 (4H, broad multiplet, aromatic-H), 3.70(1H, s, 6-aromatic-H) 5.38 (2H, broad s, NH₂), 6.19 (3H, s, OCH₃) 6.43(2H, s, NCH₂ Ar), 6.76-7.15 (2H, broad multiplet, piperidine-H),7.54-8.20 (10H, broad multiplet, piperidine-H and aromatic CH₃). Thecompound was converted to a dihydrochloride as described above whichdecomposed at about 180°-210°.

(d)5-amino-4-chloro-2-(1-(4-methoxyphenyl)piperidine-4-carboxamido)anisoleas a brown foam (75%); n.m.r. (CDCl₃), τ 1.80 (1H, s, aromatic H), 2.49(1H, broad, NHCO), 2.66-3.31 (4H, complex multiplet, aromatic H), 3.79(1H, s, 6-aromatic H), 6.09 (2H, broad s, NH₂), 6.25 (6H, s, OCH₃) 6.60(2H, s, NCH₂ Ar), 6.84-7.26 (2H, broad multiplet, piperidine H),7.59-8.31 (7H, broad multiplet, piperidine H). The compound wasconverted to a dihydrochloride, as described above which decomposes atabout 180°-210°.

EXAMPLE 6N-(4-Acetylamino-5-chloro-2-methoxyphenyl)-4-benzylpiperazine-1-carboxamide##STR18##

An acetone solution of 4-acetylamino-5-chloro-2-methoxy-benzoyl chloride(e6) (2.0 g) was added to a stirred aqueous solution of sodium azide(2.0 g) and the suspension stirred at room temperature for 30 minutes.Extraction with ethyl acetate gave4-acetylamino-5-chloro-2-methoxy-benzoyl azide (e7) (4.3 g) as a whitecrystalline solid on trituration under petrol, m.p. 135°-140°. [I.R.ν(N₃)=2140 cm⁻¹ and ν (C═O)=1645, 1705 cm⁻¹ ].

A solution of the 4-acetylamino-5-chloro-2-methoxy benzoyl azide (e7)(1.35 g) in dry toluene (30 ml) was heated to 90° for 30 minutes withstirring under dry nitrogen until the evolution of nitrogen ceased. Adichloromethane solution of 1-benzylpiperazine (0.9 g) was then added tothe cooled suspension of the isocyanate (e8) and the resulting solutionstirred at room temperature for 1 hour. The reaction mixture was thenpoured into petrol (200 ml) and the precipitated solid filtered off.Recrystallisation from toluene give theN-(4-acetylamino-5-chloro-2-methoxyphenyl)-4-benzylpiperazine-1-carboxamide(e9) (1.4 g) m.p. 174°.

EXAMPLE 7N-(4-Amino-5-chloro-2-methoxyphenyl)-4-benzylpiperazine-1-carboxamide##STR19##

A solution ofN-(4-acetylamino-5-chloro-2-methoxyphenyl)-4-benzylpiperazine-1-carboxamide(e9) (1.4 g) in ethanol (20 ml) was refluxed for 1 hour with an aqueous(4 ml) solution of potassium hydroxide (0.6 g). The solvent was removedby evaporation and the residue extracted with ethyl acetate.Chromatography of the solution (on alumina with 5% water, in chloroform)followed by evaporation of the solvent yieldedN-(4-amino-5-chloro-2-methoxyphenyl)-4-benzylpiperazine-1-carboxamide(e10).

n.m.r. (CDCl₃) τ 2.00 (1H, s, 3-aromatic-H), 2.70 (5H, s, aromatic-H),3.30 (1H, broad s, NHCO), 3.73 (1H, s, 6-aromatic-H), 6.0-6.3 (2H, broads, NH₂), 6.24 (3H, s, OCH₃), 6.4-6.7 (4H, broad multiplets-piperazinering --H), 7.4-7.7 (4H, broad multiplets-piperazine ring --H).

The free base was further characterised by conversion to a hydrochloride(30% overall), m.p. 168° (dec).

EXAMPLE 8 N-(4-Acetylamino-5-chloro-2-methoxyphenyl)-N¹-(1-benzyl-4-piperidino)urea ##STR20##

4-Acetylamino-5-chloro-2-methoxy-benzoyl azide (e7) (2.2 g) wasrearranged to the isocyanate (e8) as described in Example 6 and thenreacted with 4-amino-1-benzylpiperidine (1.56 g) by the method ofExample 6 to yield N-(4-acetylamino-5-chloro-2-methoxyphenyl)-N¹-(1-benzyl-4-piperidine)urea (e11) as a pale yellow solid (2.3 g),m.p. >230° (dec).

EXAMPLE 9 N-(4-Amino-5-chloro-2-methoxyphenyl)-N¹-1-benzyl-4-piperidine)urea ##STR21##

N-(4-Acetylamino-5-chloro-2-methoxyphenyl)-N¹-(1-benzyl-4-piperidine)urea (e11) was hydrolysed by the method ofExample 7 to yield N-(4-amino-5-chloro-2-methoxyphenyl)-N¹-(benzyl-4-piperidine)urea (e12) as a light grey solid (1.6 g) m.p.150°-153° C.

EXAMPLE 10 2-(1-Benzylpiperidine-4-carboxamido)-4-chloroanisole##STR22##

2-(1-Benzylpyridinium-4-carboxamido)-4-chloroanisole chloride (e13)(26.8 g) was hydrogenated over Adams catalyst (0.8 g) at 250 psi inethanol (500 ml) at room temperature. When hydrogen uptake ceased, thesolution was filtered, evaporated to dryness and the residue shaken witha mixture of ethyl acetate and sodium carbonate solution. The organiclayer was dried (sodium carbonate), filtered and evaporated and theresidue purified by chromatography on silica gel, eluting with gradedmixtures of light petroleum and ethyl acetate to yield after evaporation2-(1-benzylpiperidine-4-carboxamido)-4-chloroanisole (e14) (14.1 g),m.p. 84°-87° C.

[The starting material (e13) was prepared as follows:

Pyridine-4-carboxylic acid (22.9 g) was dissolved inhexamethylphosphoramide (150 ml), the solution cooled in an ice bath andthionyl chloride (14.2 ml) added. After 30 minutes2-amino-4-chloroanisole (29.4 g) in hexamethylphosphoramide (50 ml) wasadded and the mixture stirred overnight. The solution was poured intowater and basified. 4-Chloro-2-(pyridine-4-carboxamido)anisole wasfiltered off, washed well with water, dried, and crystallised from ethylacetate-light petroleum as buff prisms (38.5 g), m.p. 147°-149°.

A solution of 4-chloro-2-(pyridine-4-carboxamido)anisole (25 g) andbenzyl chloride (12 ml) in dimethylformamide (250 ml) was heated at 110°for 4 hours. The solvent was removed and the residue boiled with ethylacetate for a few minutes, then filtered off and washed well with ethylacetate. The benzylpyridinium chloride (e13) was obtained as a yellowpowder (30.0 g).]

EXAMPLE 114-Chloro-2-(1-[4-chlorobenzyl]-piperidine-4-carboxamido)anisole##STR23##

4-Chloro-1-(4-piperidine carboxamide)anisole (e15) (5 g), 4-chlorobenzylchloride (3.6 g) and potassium carbonate (3.1 g) were stirred togetherin dimethylformamide (150 ml) at room temperature for 17 hours. Thesolvent was removed and the residue taken up in a mixture of chloroformand water. The organic layer was dried (K₂ CO₃), filtered and evaporatedto dryness to yield4-chloro-2-(1-[4-chlorobenzyl]-piperidine-4-carboxamido) anisole (e16).This was converted to the hydrochloride salt which was recrystallisedfrom ethanol-ethyl acetate (7.4 g), m.p. 239°-243° C.

The starting material (e15) was prepared as follows:

4-Chloro-2-(4-pyridinecarboxamido)anisole hydrochloride (from E14) (10g) was hydrogenated over Adams' catalyst (0.25 g) at 300 psi in ethanol(250 ml) at 70° for 6 hours. The residue obtained after filtration andevaporation was taken up in a mixture of ethyl acetate and aqueoussodium carbonate, the organic layer was dried (Na₂ CO₃) filtered andevaporated to give 4-chloro-2-(piperidine-4-carboxamido)anisole as acream-coloured powder (7.4 g). (A portion was recrystallised from ethylacetate to give white prisms, m.p. 124°-126°.)

EXAMPLE 124-Chloro-2-(1-(4-methoxybenzyl)-piperidine-4-carboxamido)-5-nitroanisole##STR24##

4-Chloro-5-nitro-2-(piperidine-4-carboxamido)anisole (e17) (3.14 g),4-methoxybenzyl chloride (1.57 g) and potassium carbonate (1.4 g) werestirred together in dimethylformamide (50 ml) for 16 h. The solvent wasremoved at the pump and ethyl acetate (200 ml) and sodium hydroxide(10%, 200 ml) were added to the residue. The ethyl acetate extract waseluted through alumina and the filtrate evaporated to yield a brownresidue, which crystallised as brown prisms from ethyl acetate-petrolether (b.p. 60°-80°), (2.96 g, 68%) m.p. 138°-142°.

Similarly prepared was4-chloro-2-[1-(4-methylbenzyl)piperidine-4-carboxamido]anisolehydrochloride monohydrate, white prisms (71%), m.p. 222°-225°.

The starting material (e17) was prepared as follows:

4-Chloro-2-(piperidine-4-carboxamido)anisole (10.4 g) was dissolved in amixture of acetic acid (100 ml) and concentrated sulphuric acid (5 ml).Fuming nitric acid (2.1 ml) was added dropwise, keeping the temperaturebelow 30°. The solution was stirred at room temperature for 2 hr, pouredonto crushed ice (ca 500 ml) and basified with 40% sodium hydroxide. Themixture was extracted with ethyl acetate (2×250 ml), the extracts dried(K₂ CO₃) and solvent removed at the pump. The brown residue wascrystallised from ethyl acetate and petroleum ether (b.p. 60°-80°),giving 4-chloro-5-nitro-2-(piperidine-4-carboxamido)anisole as brownplates (e17) (9.9 g, 82%), m.p. 167°-170°.

EXAMPLE 13 Compositions

(a) Tablets of the following composition may be prepared:

    ______________________________________                                        5-Amino-4-chloro-2-                                                           (1-benzylpiperidine)-4-                                                       carboxamido)anisole                                                           dihydrochloride         25 mg                                                 Microcrystalline cellulose                                                                            123 mg                                                Magnesium stearate      2 mg                                                  ______________________________________                                    

(A similar tablet may be produced containing an equivalent amount of themono-hydrochloride.)

(b) Hard gelatin capsules may be prepared containing the following:

    ______________________________________                                        5-Amino-4-chloro-2-                                                           (1-benzylpiperidine-4-                                                        carboxamido)anisole                                                           mono-hydrochloride      25 mg                                                 Lactose                 70 mg                                                 Sodium lauryl sulphate  5 mg                                                  ______________________________________                                    

(A similar capsule formulation may be produced containing an equivalentamount of the di-hydrochloride.)

DESCRIPTION 1 Pharmacology

a. The compound of Example 3 was active on the amphetamine stereotypytest in rats [based on Janssen et al, Arzenimittelforsch, 15, 104-117,(1966)] where it had an ED₅₀ of 0.2 mg/kg when administeredsub-cutaneously. On the anti-catepressan test [based on Costal et al,Europ. J. Pharmacol., 18, 83-94 (1972)] the compound of this Example hadan ED₅₀ of 5 mg/kg per oral. The LD₅₀ of the compound of Example 3 isabout 500 mg/kg per oral in the mouse.

b. 5-Amino-4-chloro-2-(1-benzylpiperidine-4-carboxamido) anisole and itssalts have anti-psychotic or neuroleptic activity as judged by theinduction of amphetamine induced stereotypy test. This compound and itssalts are of particular interest because they show a weaker propensityto induce catalepsy (an indicator of potential extrapyramidol sideeffects) relative to its anti-stereotypy activity than such clinicallyused compounds as haloperidol or chlorpromazine. These results are shownin the following Table 1.

                  TABLE 1                                                         ______________________________________                                                   ED.sub.50 (mg/kg S.C.)                                                          Induction of                                                     Antagonism   amphetamine                                                                              Induction                                                                              Ratio                                        of           induced    of       catalepsy                                    compound     stereotypy catalepsy                                                                              anti-sterotypy                               ______________________________________                                        5-Amino-4-chloro-2                                                            (1-benzylpiperidine-                                                                       0.2        6.0      30                                           4-carboxamido)                                                                anisole or its mono-                                                          or di-hydrochloride                                                           Haloperidol  0.05       0.3      6                                            Chlorpromazine                                                                             1.0        3.0      3                                            ______________________________________                                    

What we claim is:
 1. A compound of the formula: ##STR25## and theN-oxides and the pharmaceutically acceptable salts thereof wherein R₁ isphenyl unsubstituted or substituted by fluoro chloro, bromo, alkyl of 1to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms;R₂ is hydrogen oralkyl of 1 to 4 carbon atoms; R₃ is hydrogen, nitro, amino, ##STR26## inwhich R₄ is alkyl of 1 to 4 carbon atoms unsubstituted or substitutedwith up to three chlorine atoms or with three fluorine atoms on the samecarbon atoms; R₅ is alkyl of 1 to 4 carbon atoms n has a value of 0, 1or
 2. 2. A compound as claimed in claim 1 wherein R₁ is phenyl,p-chlorophenyl, p-methylphenyl or p-methoxyphenyl.
 3. A compound asclaimed in claim 1 wherein R₁ is phenyl.
 4. A compound as claimed inclaim 1 wherein R₂ is hydrogen, methyl, ethyl, n-propyl or n-butyl.
 5. Acompound as claimed in claim 1 wherein R₂ is hydrogen or methyl.
 6. Acompound as claimed in claim 1 wherein R₂ is hydrogen.
 7. A compound asclaimed in claim 1 wherein n is
 0. 8. A compound as claimed in claim 1wherein R₂ is hydrogen, n is 0 and R₁ is phenyl.
 9. A compound asclaimed in claim 1 wherein R₃ is hydrogen.
 10. A compound as claimed inclaim 1 wherein R₃ is nitro.
 11. A compound as claimed in claim 1wherein R₃ is amino, NHCOR, or NHCO₂ R₄ where R₄ is alkyl of 1 to 4carbon atoms.
 12. A compound as claimed in claim 1 wherein R₃ is amino,acetylamino, propionylamino, methoxycarbonylamino orethoxycarbonylamino.
 13. A compound as claimed in claim 1 wherein R₃ isamino or acetylamino.
 14. A compound as claimed in claim 1 wherein R₃ isamino.
 15. A compound of the formula: ##STR27## or a pharmaceuticallyacceptable salt thereof wherein R₁ is phenyl unsubstituted orsubstituted with fluoro, chloro, bromo, alkyl of 1 to 3 carbon atoms oralkoxy of 1 to 3 carbon atoms;R₂ is hydrogen or alkyl of 1 to 4 carbonatoms; n is 0, 1 or 2; R₅ is alkyl of 1 to 4 carbon atoms; and R₆ ishydrogen, COR₄ or CO₂ R₄ wherein R₄ is alkyl of 1 to 4 carbon atomsunsubstituted or substituted with one, two or three chlorine atoms orwith three fluorine atoms on the same carbon atom.
 16. A compound asclaimed in claim 15 wherein R₆ is hydrogen.
 17. A compound as claimed inclaim 16 wherein R₁ is phenyl, p-chlorophenyl, p-methoxyphenyl orp-methylphenyl.
 18. A compound as claimed in claim 16 wherein R₁ isphenyl.
 19. A compound as claimed in claim 16 wherein R₂ is hydrogen,methyl, ethyl, n-propyl or n-butyl.
 20. A compound as claimed in claim16 wherein R₂ is hydrogen or methyl.
 21. A compound as claimed in claim16 wherein R₂ is hydrogen.
 22. A compound as claimed in claim 16 whereinn is
 0. 23. A compound as claimed in claim 1 in the form of the freebase.
 24. A compound as claimed in claim 1 in the form of apharmaceutically acceptable acid addition salt.
 25. A compound asclaimed in claim 16 in the form of a mono-acid addition salt.